Statins decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons
Statins decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons
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DOI：
10.1124/jpet.107.132795
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发表时间：
2008-03-01
影响因子：
3.5
通讯作者：
Lein, Pamela J.
中科院分区：
文献类型：
--
作者：
Bucelli, Robert C.;Gonsiorek, Eugene A.;Lein, Pamela J.
临床和实验观察表明，他汀类药物可用于治疗以神经源性炎症为主的疾病，但对介导这种潜在治疗作用的机制知之甚少。在这项研究中，我们测试了他汀类药物直接作用于感觉神经元以减少促炎神经肽（特别是降钙素基因相关肽（CGRP）和P物质）表达的假设。采用免疫细胞化学方法检测背根神经节（DRG）CGRP和P物质的表达收获自成年雄性大鼠和来源于胚胎大鼠DRG的感觉神经元的原代培养物。全身给药他汀类药物的相关剂量显着降低CGRP和P物质在DRG中的水平在体内。在培养的感觉神经元中，他汀类药物阻断骨形态发生蛋白（BMP）诱导的CGRP和P物质的表达，并降低这些神经肽在BMP预处理的感觉神经元中的表达。这些作用是浓度依赖性的，并且与对细胞存活或轴突生长的作用无关。他汀类药物抑制神经肽的表达被逆转补充甲羟戊酸和胆固醇，但不是类异戊二烯前体。BMP信号通过Smad激活，胆固醇耗竭抑制Smad1磷酸化和核转位。这些研究结果确定了一种新的行动，他汀类药物涉及通过胆固醇消耗和减少Smad1激活的感觉神经节中的促炎性神经肽表达下调，并表明他汀类药物可能是有效的衰减神经源性炎症。
Clinical and experimental observations suggest that statins may be useful for treating diseases presenting with predominant neurogenic inflammation, but the mechanism(s) mediating this potential therapeutic effect are poorly understood. In this study, we tested the hypothesis that statins act directly on sensory neurons to decrease expression of proinflammatory neuropeptides that trigger neurogenic inflammation, specifically calcitonin gene-related peptide (CGRP) and substance P. Reverse transcriptase-polymerase chain reaction, radioimmunoassay, and immunocytochemistry were used to quantify CGRP and substance P expression in dorsal root ganglia (DRG) harvested from adult male rats and in primary cultures of sensory neurons derived from embryonic rat DRG. Systemic administration of statins at pharmacologically relevant doses significantly reduced CGRP and substance P levels in DRG in vivo. In cultured sensory neurons, statins blocked bone morphogenetic protein (BMP)-induced CGRP and substance P expression and decreased expression of these neuropeptides in sensory neurons pretreated with BMPs. These effects were concentration-dependent and occurred independent of effects on cell survival or axon growth. Statin inhibition of neuropeptide expression was reversed by supplementation with mevalonate and cholesterol, but not isoprenoid precursors. BMPs signal via Smad activation, and cholesterol depletion by statins inhibited Smad1 phosphorylation and nuclear translocation. These findings identify a novel action of statins involving down-regulation of proinflammatory neuropeptide expression in sensory ganglia via cholesterol depletion and decreased Smad1 activation and suggest that statins may be effective in attenuating neurogenic inflammation.